Rationale: Relatively little is known about the hepatotoxicity of pyrazinamide. Objectives: We compared continuation-phase regimens incorporating pyrazinamide, isoniazid and/or rifampin with those containing isoniazid and rifampin to evaluate the hepatotoxicity of pyrazinamide. Methods: Cohort and nested case-control analyses were conducted on a cohort of 3007 patients with active TB managed at government chest clinics under a TB control program with treatment started from January 1 to June 30, 2001 inclusive. Cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when serum alanine transaminase exceeded three times the upper limit of normal. Each case was matched by sex and age with three controls selected randomly from the rest of the cohort. Treatment regimens of cases within four weeks preceding hepatotoxicity were compared with those of matched controls in comparable periods relative to the date of commencing treatment. Results: Hepatotoxicity occurred in 150 (5.0%) patients at any time including 48 (1.6%) cases. From 12 or more weeks after starting treatment, the estimated risk of hepatotoxicity was 2.6% for regimens incorporating pyrazinamide, isoniazid and/or rifampin, and 0.8% for standard regimens containing isoniazid and rifampin. Multivariable conditional logistic analysis showed a significant association between hepatotoxicity and, respectively, hepatitis B, previous hepatotoxicity, and treatment regimens. The adjusted odds ratio (95% confidence interval) of hepatotoxicity for regimens incorporating pyrazinamide, isoniazid and/or rifampin relative to standard regimens was 2.8 (1.4-5.9). Conclusions: Adding pyrazinamide to isoniazid and rifampin increases the risk of hepatotoxicity appreciably.